Prevalence and factors associated with hepatitis C among pregnant women in China: a cross-sectional study

Pregnant women infected with HCV should be given attention due to their special physiological stage and the effect on offspring health. To examine the prevalence of HCV infection among pregnant women in part of China and explore relevant factors during pregnancy, a cross-sectional study was conducted in four maternal and children health care institutions (MCHC) in Guangdong, Hunan and Chongqing. Pregnant women who were delivered, induced or spontaneous abortion were included and relevant information was collected through the Hospital Information System. Results showed that the prevalence of HCV among pregnant women in four MCHCs was 0.11% (95% CI 0.09–0.13%). Age, occupations, regions, syphilis-infection, intrahepatic cholestasis of pregnancy (ICP), and placenta previa were significant factors (all P < 0.05). Age and syphilis-infection were positively correlated with HCV infection (Z = 3.41, P = 0.0006; OR = 18.16, 95% CI 9.34–35.29). HCV and HBV infection were risk factors of ICP (OR = 4.18, 95% CI 2.18–8.04; OR = 2.59, 95% CI 2.31–2.89). Our study indicates that the prevalence of HCV among pregnant women in the three provinces(city) was low compared with the general population in China. Older age and syphilis-infection increased the risk of HCV infection during pregnancy. HCV infection was a risk factor of ICP. Generally, we need keep a watchful eye on HCV infection and relevant factors mentioned above during pregnancy in clinic, especially those also infected with syphilis. HCV testing based on risk factors is recommended in antenatal care and obstetrics.

www.nature.com/scientificreports/ women are infected by HCV 2 . Mother-to-child transmission is one of the main transmission routes of HCV 3 , with the rate of 5.8% (95% CI 4.2%-7.8%) worldwide 4 . As a curable chronic infectious disease, perinatal hepatitis C infection has a spontaneous clearance rate (25-30%) 5 , so mother-to-child transmission of HCV has been ignored. However, in fact, once diagnosed with HCV infection, more than 80% of newborns will show chronic symptoms 6 , in which 30% will develop clinical symptoms in childhood or adulthood, and are at high risk of liver cirrhosis and hepatocellular carcinoma (HCC) 7 . In addition, hepatitis C infection is strongly associated with adverse pregnancy outcomes, including fetal growth restriction, low birth weight, congenital abnormalities, and preterm birth 4 . Therefore, understanding the prevalence of HCV among pregnant women and exploring risk factors should be given high importance.
In 2016, WHO proposed the goal of eliminating viral hepatitis as a public health threat by 2030 8 -a 90% reduction in new infections and a 65% reduction in mortality. Whereas most studies on viral hepatitis infection primarily focused on HBV 9 or specially HCV exposed populations such as people who inject drugs (PWID) and men who have sex with men (MSM) [10][11][12] , studies among pregnant women were scarce. To achieve the goal of eliminating HCV as a public health threat, reducing the disease burden of society and decreasing new HCV infections, study on HCV pregnant women and HCV mother-to-children transmission is essential. In this study, we investigated the pregnant women who had been admitted in selected maternal and children health care institutions (MCHC) in some regions of China by collecting data from the Hospital Information System (HIS), so as to understand the prevalence of HCV infection among pregnant women and its associated factors.

Participants and method
Study sites and participants. Taking  Method. All the data were collected from the Hospital Information System (HIS) of obstetrics, hospital laboratory or infection department in the study sites. The investigators were trained uniformly and arranged to export information in the same way. Participants were not involved in the design, or conduct, or reporting, or dissemination plans of our research. All methods were performed in accordance with the relevant guidelines and regulations. Designed by National Center for Women and Children's Health, Chinese Center for Disease Control and Prevention, and completed by trained collectors from the study sites, the registration form contained infor-  Statistical analyses. Quantitative variables were expressed as mean ± SD, and analyzed using student's t-test. Categorical variables were expressed as frequencies and percentages. The χ 2 test and exact Fishers test were applied for the analysis of categorical variables. Statistical significance level was set at a two-sided p < 0.05.
Stepwise logistic regression was performed to identify associated factors of HCV infection. To explore whether HCV infection may exacerbate the occurrence of adverse pregnancy outcomes or related complications, model fitness was tested using multivariate logistic regression. All the analyses were performed on SAS 9.4.
Ethical approval. This study has been approved by the Ethics Committee of Maternal and Child Health Center, Chinese Center for Disease Control and Prevention (Approval No.: FY2021-16).

Results
Sociodemographic characteristics. As HCV screening has not been included into the scope of routine prenatal health care in China, the linked database contained 15,297 cases without HCV testing results and the prenatal screening rate was 90.20% among the four study sites. After excluding those duplicate cases and those without HCV testing results, the total sample consisted of 137,901 individuals, with ages ranging from 13 to 59 (30.30 ± 4.14). Of these, 20,492 were elder than 35 years old (14.86%), and 273 were younger than 20 years old (0.20%). Most individuals were unemployed (33.14%) and national staff (39.25%). As for the regional distribution, participants were from three provincial regions, namely Guangdong (38.50%), Hunan (28.33%) and Chongqing (33.17%). The majority of them were the Han nationality (96.03%), see in Table 1.

Prevalence of HCV among pregnant women in different dimension.
The positive rate of HCV antibody among the participants was 0.11% (95% CI 0.09%-0.13%). As shown in Table 1 and Fig. 2, the preva-

HCV and syphilis or HBV co-infection. A number of HCV-infected patients with syphilis or HBV co-
infection was identified. There were 5 pregnant women co-infected HCV and HBV, 9 co-infected HCV and syphilis and 2 infected all three viruses simultaneously. Therefore, the co-infection rate of HBV and syphilis among HCV-infected patients was 4.86% and 7.64% respectively.  (Table 4).

Discussion
Hepatitis C virus infection may lead to cirrhosis, liver failure, and hepatocellular carcinoma, it will also transmit from mother to offspring 13 . Thus, it is vitally important to investigate the prevalence of HCV infection among pregnant women. Nowadays, routine HCV screening is currently not widely recommended during pregnancy for the reason of cost-effectiveness and the evidence of spontaneous clearance in Japan, Canada, China and some other countries [14][15][16] . From the results we analyzed, the HCV prenatal screening rate during pregnancy was 90.20%, which was lower than the rate of hepatitis B virus, HIV and syphilis during pregnancy in China [17][18][19] .
In this study, the positive rate of HCV antibody in pregnant women is 0.11% (95% CI 0.09%-0.13%), which is similar to those reported in local studies. For example, surveillance data from Zhongshan city in Guangdong province showed that the proportion of pregnant women infected with HCV gradually decreased from 2009 to 2019, and the HCV positive rate in 2018 was 0.25%, 0.00% in 2019 20 . A meta-analysis by Ma et al. on the positive rate of hepatitis C antibody among pregnant women in China from 2008 to 2018 showed the rate was 0.235% (95% CI 0.189%-0.286%) 21 . In the general population in China, the prevalence of HCV is 0.38% (95% CI 0.23%-0.53%) 22 , which is higher than what we found in pregnant women. While compared with other counties, the rate seems to be close to developed countries but lower than low and middle-income ones. The reported prevalence of maternal hepatitis C virus infection in the United States was 0.24% in 2020 while such rate was much higher in Africa 23 (3.4%), Pakistan 24 (2.22%) and Egypt 25 (6.1%).
It would be noteworthy to identity those sociodemographic characteristics that were associated with higher risk of HCV infection. Older age was found to be a significant factor of HCV positive rate in the present study www.nature.com/scientificreports/  Table 3. Multivariate Logistic regression model analysis of HCV associated factors among pregnant women in three provinces. a "No" was used as the reference group.  25 and Costa et al. 26 found that older age was one of the most important risk factors for HCV infection among pregnant women. However, Dagnew et al. 27 reported a higher HCV prevalence among young pregnant women, attributing to the fact that young females are more active sexually and more probable to expose to multiple sex. Our findings also showed that region and occupation were significant factors of HCV infection. This could be attributed to differences in the geographical location, various socioeconomic status and lack of awareness of HCV infection among certain regions. Analyses of gestational complications and adverse neonatal outcomes in relation to HCV infection during pregnancy can be complex as it's hard to discern whether the infection is a direct influence or a potential confounding factor. Nevertheless, we confirmed that HCV infection was found to be one of the risk factors of ICP during pregnancy, which was in agreement with the extant literature that indicated [28][29][30] that ICP was more prevalent in patients, including pregnant women, with chronic HCV infection. Besides, no association between gestational diabetes and HCV infection was observed in our study, whereas Samir Rouabhia et al. 31 believed that HCV exacerbated insulin resistance or diabetes leading to a reduced ability to fight infection, leading to an increased risk of type 2 diabetes among those with HCV infection during pregnancy. We also found placenta previa and HCV infection were related but HCV infection had no effect on the occurrence of placenta previa. Similarly, Piffer et al. 32 found no significance for eclampsia, premature rupture of membranes and placenta previa. It is reported 33,34 that the adverse neonatal outcomes like preterm birth and low birth weight (LBW) were more likely to occur in mothers with HCV, however such finding was not replicated in the present study.
It is intriguing that despite the evidence that coinfection with sexually transmitted diseases 34-37 could aggregate the prevalence of HCV due to the similar transmission way and similar pathological mechanism, such association was not significant in the present study in terms of HBV co-infection and there were no cases with HCV and HIV co-infection. While syphilis co-infection was identified as a risk factor from the data analysis, the co-infection rate of HBV and syphilis in HCV-infected participants was 4.86% and 7.64%, respectively. The coinfection rate was diverse from those reported in the extant literature 38,39 , which reports a HBV rate of 5.7% in hemodialyzers with HCV infection, a HIV rate of 3.9% in pregnant women, and syphilis rate of 0.5% in unpaid blood donors. The possible reasons for such discrepancies may be that the participants were mostly from the urban areas, with possibility higher level of education, health awareness and financial situation. From the perspective of the clinic, pregnant women who were coinfected with sexually transmitted diseases should be managed and taken seriously. The combination of screening and follow-up monitoring should be taken into consideration.
There were some limitations that should be noted. Firstly, data were only collected from three provinces or cities due to time and funding limitations, therefore findings may not be generalized to the whole pregnant women population in China. In addition, the present study was cross-sectional in nature, which cannot reflect the casual relationship. Meanwhile, there were duplicates (2950) and cases without HCV testing results (15,297) during data collection, which may be due to insufficient on-site supervision and the low screening rate of prenatal HCV. Indeed, HCV prenatal screening could help to know the prevalence of HCV among pregnant women and their hepatitis C virus status, which facilitates the clinical identification and management of key maternal outcomes timely. More studies on cost-effectiveness and disease burden is needed to decide whether universal screening of HCV is recommended in the clinic. Table 4. Multivariate logistic regression model analysis of associated factors of ICP among pregnant women in three provinces. a "No" was used as the reference group. www.nature.com/scientificreports/ Findings from the present and previous studies 14 indicate that HCV testing based on the presence of risk factors may be warranted among pregnant women in antenatal care clinic as well as obstetrics department. Besides, prevention and health care knowledge about HCV should be designed to educate and promote in communities, hospitals, schools, etc. Moreover, longitudinal studies on HCV infection among pregnant women should be carried out based on data support of this study to understand the mechanism of mother-to-child transmission of HCV, explore the prevention of neonatal infection with HCV, and clarify the risk factors of HCV infection. In order to reach the WHO goal of HCV elimination, efforts and support from all sectors of society are necessary.

Conclusion
The prevalence of HCV infection among pregnant women in Guangdong province, Hunan province and Chongqing city was 0.11% (95% CI 0.09%-0.13%). This indicator was at a low level compared with the general population in China. Age, region and syphilis infection were significantly associated with HCV infection during pregnancy. And HCV infection was found to be one of risk factors of intrahepatic cholestasis of pregnancy (ICP). In conclusion, pregnant women with HCV should be paid high attention in clinic, especially those infected with syphilis at the same time. HCV testing based on risk factors is recommended so as to protect the health of pregnant women and their infants.

Data availability
The data presented in this study are available on request from the corresponding author.